Lecture 28 - Immunology III

Question 1

What are T-cells and their receptors?

Answer 1

T-cells make up a ‘cellular’ defence mechanism, that detect and respond to antigens presented by specialised antigen-presenting cells.

Question 2

What do cytotoxic T-cells do?

Answer 2

directly kill infected host cells

Question 3

What do helper T-cells do?

Answer 3

activate macrophages, dendritic cells, B-cells and cytotoxic cells by secreting a variety of cytokines and displaying a variety of co-stimulatory proteins on their surface.

Question 4

What do regulatory T-cells do?

Answer 4

use similar strategies to inhibit inhibit the function of helper T-cells, cytotoxic T-cells and dendritic cells

Question 5

How do T-cells provide specificity?

Answer 5

T-cells use T-cell receptors (TCRs) to provide specificity to identify antigens. TCRs are immunoglobulins and contain constant and variable domains as well as hyper-variable loops much like antibodies.

Question 6

What generate T-cell receptor diversity?

Answer 6

• T-cell receptor diversity is generated by V(D)J-like recombination & junctional diversification in the thymus to give diversity of 1 x 10^8 (this decreases with age by 2-5 fold).
• Membrane bound (transmembrane bound) - presented on the plasma membrane of the T-cells

Question 7

What are T-cells activated by?

Answer 7

Partly degraded antigens displayed on the surface of antigen-presenting cells

Question 8

What happens to MHC (major histocompatibility complex) proteins on antigen presenting cells?

Answer 8

They bind to the peptide fragments and carry them to the cell surface where T-cells can recognise them

Question 9

How can antigen presenting dendritic cells either ‘activate’ or ‘tolerise’ T-cells?

Answer 9

• activating dendritic cells present 3 proteins: MHC with foreign antigen, stimulating ligands and cell-cell adhesion molecules
• tolerising dendritic cells present self-antigens on the MHCs but don’t include the co-stimulatory activator protein
• Activating dendritic cells present foreign antigens along with co-stimulatory signals to activate T cells.
• Tolerizing dendritic cells present self-antigens but lack these co-stimulatory signals, leading to immune tolerance and preventing an attack on the body’s own cells.

Question 10

What are the different classes of MHC proteins?

Answer 10

Class 1 - activating cytotoxic T-cells
Class 2 - activating Helper and Regulator T-cells

Question 11

Explain how Class I & II are similar?

Answer 11

Transmembrane heterodimers with extracellular N-terminal domains that bind a very large number of different peptides.

Question 12

Why does each MHC have to be able to bind a very large number of different peptides?

Answer 12

Any individual can only make a narrow range of MHC proteins, which may be able to present peptide fragments from almost any foreign protein to T cells.

Question 13

How can there be a failure of the first line of defence?

Answer 13

‘opportunistic’ infections many of which have developed ways to evade adaptive immune responses

Question 14

What is Candida albicans?

Answer 14

a yeast that usually lives on skin, mouth, gut, vagina without issues, but can become pathogenic

• grows as several forms including ‘normal’ yeast cells and pseudoyphal filamentous forms
• phagocytosis by macrophages can induce switch to hyphae form

Question 15

What is Staphyloccocus aureus?

Answer 15

a Gram-positive spherical bacterium, frequently found in the upper respiratory tract and on the skin

• produces Protein A (A for aureus) - a 42kDa cell wall surface protein that binds to the constant domains of IgGs.
• Bacteria are covered with ‘self’ proteins and no longer recognised by innate immune system.

Question 16

What is Human Immunodeficiency Virus (HIV)?

Answer 16

an RNA lentivirus that specifically infects T-helper cells, dendritic cells and macrophages expressing the CD4 receptors/

• infected immune cells no longer function AND trigger immune responses that trigger T-cells to target cells absolutely required for adaptive immune system function.
• this results in immune deficiency and leads to infections (e.g. Candida & Aspergillus) and cancers rarely seen in those with intact immune systems.
• Kaposi’s sarcoma is caused by herpesvirus 8
  (HHV-8), a relatively common virus that only cause cancer in people with a weakened immune system

Question 17

What occurs in type 1 diabetes?

Answer 17

The immune system develops killer T-cells that attack insulin-producing beta-cells within the Islets of Langerhans within the pancreas.

Question 18

What occurs in Multiple Sclerosis?

Answer 18

The immune system responds to proteins within the myelin sheath of neurons within the CNS. Associated with a range of symptoms, progressive loss of myelination can ultimately be fatal.

Question 19

What are StarMS & MIST?

Answer 19

StarMS & MIST clinical trials underway in Sheffield to treat Multiple Sclerosis with stem cell transplant to ‘reset’ the immune system and redefine ‘self’ antigens.

Question 20

What are examples of auto immune inflammatory diseases?

Answer 20

• rheumatoid arthritis
• psoriasis
• Crohns disease
• inflammatory bowel disease (IBD)
• ulcerative colitis

Question 21

How does auto immune inflammatory diseases come about?

Answer 21

Defects in the ‘self-tolerance’ process leading to the production of antibodies that trigger inflammatory responses by the innate immune system.

Question 22

How are immunity and cancer related?

Answer 22

HIV & immunosuppressed patients (e.g. organ transplant recipients) have increased rates of Karposi’s sarcoma, basal cell carcinoma & hepatocellular carcinoma

Immune competence decreases with age - “immunosenescence” - implying that decreased immunosurveillance against cancer contributes to increased disease in the elderly (age is the biggest risk factor for cancer).

In mouse transplantation models, in syngeneic hosts (immunologically compatible), normal tissues are accepted but tumours are rejected. So suggesting the existence of tumour-specific antigens which can be recognised as non-self

Overall, there seems to be compelling evidence that our immune systems identify and kill cancerous (and pre-cancerous) cells.

Question 23

What has histology routinely identified that is consistent with the cancer immune surveillance model?

Answer 23

The cancer immune surveillance model suggests that the immune system helps to detect and fight cancer cells.

Tumour infiltrating lymphocytes (TILs) are immune cells (like T cells) that have moved into the tumor tissue in an attempt to attack the cancer cells.

The presence of TILs in a tumor is a sign that the immune system is trying to recognize and destroy the cancer.

Histology (the study of tissue) can identify these immune cells in tumor samples, supporting the idea that the immune system is actively involved in responding to cancer.

Question 24

What are the 3 stages that ‘cancer immunoediting’ is thought to be composed of?

Answer 24

1. Elimination phase - tumour cells are killed by NK, CD4+ and CD8+ cells
2. A state of equilibrium between immune and tumour cells
3. When the immune system is unable to destroy the tumour cells, they ‘escape’ leading to clinically detectable tumours - likely after in vivo evolution of cancer cells able to bypass surveillance mechanisms.

Question 25

Given the existing links between the immune system and cancer, how can the capability of the adaptive immune system be enhanced?

Answer 25

• stimulating, or boosting, the immune system so it is more effective at identifying and attacking cancer cells
• approaches to help restore or improve how the immune system works to find and attack cancer cells

Question 26

What are the limits on the immune system’s ability to fight cancer on its own?

Answer 26

• the immune system doesn’t see the cancer cells as foreign because the cells aren’t different enough from normal cells
• the immune system recognises the cancer cells, but the response might not be strong enough to destroy the cancer
• cancer cells themselves can also give off substances that keep the immune system from finding and attacking them

Question 27

What are the different types of cancer immunotherapy?

Answer 27

• checkpoint inhibitors - takes the “brakes” off the immune system
• cytokines - to stimulate the immune cells to attack cancer
• immunomodulators - boosts parts of the immune system
• cancer vaccines - vaccines that direct an immune response designed to prevent a specific cancer epitope or cancer causing pathogen (e.g. HPV).
• Monoclonal antibodies (mAbs) - directed against cancer specific antigens
• Oncolytic viruses - viruses that have been modified in a lab to infect and kill certain tumour cells.
• CAR-T cell therapy

Question 28

What is chimeric antigen receptor (CAR) T-cell therapy?

Answer 28

approach that takes the patients T cells and infects them (ex vivo) with a recombinant virus that causes the expression of a T-cell receptor, with an antibody-derived variable (antigen binding) domain specific to a tumour antigen. This generates T-cells able to attach to tumour cells. These are transfused back into the patient so they can find, attach and kill the cancer.

Question 29

What is a side effect of an immunotherapy - e.g. checkpoint inhibitors?

Answer 29

Graf Verses Host Disease (GVHD) - a relatively common side effect of heterologous haematopoietic stem cell / bone marrow transplantation where transplanted T cells will attack and kill the new host. Also can occur as a side effect of immunotherapy - e.g. autoimmune reactions or immune-related side effects (e.g. GVHD)